HSV-2-Specific Human Female Reproductive Tract Tissue Resident Memory T Cells Recognize Diverse HSV Antigens

Abstract

Antigen-specific TRM persist and protect against skin or female reproductive tract (FRT) HSV infection. As the pathogenesis of HSV differs between humans and model organisms, we focus on humans with well-characterized recurrent genital HSV-2 infection. Human CD8+ TRM persisting at sites of healed human HSV-2 lesions have an activated phenotype but it is unclear if TRM can be cultivated in vitro. We recovered HSV-specific TRM from genital skin and ectocervix biopsies, obtained after recovery from recurrent genital HSV-2, using ex vivo activation by viral antigen. Up to several percent of local T cells were HSV-reactive ex vivo. CD4 and CD8 T cell lines were up to 50% HSV-2-specific after sorting-based enrichment. CD8 TRM displayed HLA-restricted reactivity to specific HSV-2 peptides with high functional avidities. Reactivity to defined peptides persisted locally over several month and was quite subject-specific. CD4 TRM derived from biopsies, and from an extended set of cervical cytobrush specimens, also recognized diverse HSV-2 antigens and peptides. Overall we found that HSV-2-specific TRM are abundant in the FRT between episodes of recurrent genital herpes and maintain competency for expansion. Mucosal sites are accessible for clinical monitoring during immune interventions such as therapeutic vaccination.

Varicella-zoster virus proteome-wide T-cell screening demonstrates low prevalence of virus-specific CD8 T-cells in latently infected human trigeminal ganglia

“…We then assayed the respective short-term TG-TCL for IFNγ secretion in response to incubation with the HLA-I matched aAPC. We have previously applied this platform to uncover the targets and diversity of HSV- and VZV-specific T-cells in human blood and other tissues in an unbiased way [ 16 , 19 , 25 – 27 ]. While all TG-TCL responded strongly to the control mitogen PHA-P, demonstrating their ability to secrete IFNγ, only 2 of 10 TG-TCL showed VZV-protein specific CD8 T-cell reactivity: the TG-TCL of subject TG04 and TG07 responded to VZV ORF29 and ORF9, respectively (Fig.…”

Novel Adjuvant S-540956 Targets Lymph Nodes and Reduces Genital Recurrences and Vaginal Shedding of HSV-2 DNA When Administered with HSV-2 Glycoprotein D as a Therapeutic Vaccine in Guinea Pigs

“…These impressive results were achieved using only a single immunogen, gD2. Adding other immunogens, particularly immediate early, tegument, and/or capsid proteins that act as effective T cell antigens, may further enhance the efficacy of a therapeutic vaccine [ 14 , 15 , 16 , 17 , 18 , 19 ].…”

“…Achieving the goal of outperforming acyclovir/valacyclovir will likely require the selection of immunogens and adjuvants that stimulate potent T cell responses [ 14 , 15 , 16 , 17 , 18 , 19 ]. Herein, we describe immune responses and outcomes using a novel adjuvant, S-540956, developed by Shionogi & Co., Ltd. (Osaka, Japan).…”

Therapeutic vaccines for herpesviruses

“…In 2001, Koelle et al studied virus-specific T cell responses from genital lesions of 3 patients and found that the most common responses were to tegument proteins UL47, UL49, and ICP0 ( 27 ). A follow-up study of genital tissue from 8 patients found that the most T cell common responses were to gD (6 patients), gB and UL39 (4 patients), and UL23 (the viral thymidine kinase, 3 patients) ( 28 ).…”